Amyloidosis is a general term that describes a number of diseases characterised by extracellular deposition of protein fibrils which form numerous ‘amyloid deposits’. These plaque-like deposits may occur in localised sites, such as the brain or systemically. The fibrillar composition of these deposits is an identifying characteristic for the various forms of amyloid disease. The following diseases and their associated protein have been identified as amyloid diseases: Diabetes mellitus type 2 (amylin); Alzheimer's disease (Aβ 39-42); Parkinson's disease (alpha-synuclein); Huntington's disease (huntingtin); Creutzfeldt-Jakob disease (PrP in cerebrum); congestive heart failure (PrP or transthyretin) and Bovine spongiform encephalopathy (PrP). Due to recent reports, Age related Macular Degeneration, ‘AMD’, is a further condition which may be characterized by amyloid deposits.
Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. AD is characterised by the presence of distinctive lesions in the patient's brain. These brain lesions include abnormal intracellular filaments called neurofibrillary tangles, and extracellular deposits of amyloid plaques. Amyloid deposits are also present in the walls of cerebral blood vessels of Alzheimer's patients. The major constituent of amyloid plaques has been identified as a 4 kilodalton peptide (39-43 residues) called beta-amyloid peptide (‘Abets’ or ‘Aβ’). Alzheimer's disease brain tissue is characterised by Abeta plaques and observations suggest that Abeta deposition contributes to the destruction of neurons. Abeta has been shown to be toxic to mature neurons both in culture and in vivo.
Currently, there is no medication capable of curing or stopping the progression of any amyloid diseases, including AD. Therapies for AD such as inhibition of acetylcholinesterase (AchE)2 activity and antagonisism of N-methyl-D-aspatarte (NMDA) receptors produce only modest symptomatic improvements in some patients. Other therapeutic approaches currently in clinical development aim to control the levels of Aβ amyloid in the brain, either by immunization or through pharmacological manipulation. Drugs that target BACE and y-secretase, the two enzymes responsible for Aβ production have concern due to side-effects of secretase inhibition since these enzymes are not specific and process a variety of substrates including the NOTCH protein.
It has been reported that the aggregated Abeta peptide has redox properties and can generate reactive oxygen species, which attack enzymes and possibly cell membranes, causing neurotoxicity and brain cell death. It has also been reported that the coordination of metal ions such as copper and zinc accelerates ABeta aggregation and generates reactive oxygen species and hydrogen peroxide. Studies have shown that a range of commonly available metal chelators (TPEN, EGTA and bathcuproine) with a reasonable affinity for Cu, Zn and Fe can solubilize deposited ABeta from post-mortem brain tissue. A potential limiting factor is that treatment with metal chelators is by definition non-specific. While limits on metal-binding affinities and tissue selectivity reduce the effects of this non-selectivity, the metal ions targeted are ubiquitous and essential and there are inherent risks associated with their non-discriminate removal.
The cure or disruption of amyloid diseases, particularly Alzheimer's disease, is further withheld by a lack of accurate and usable imaging and patient diagnostic techniques. For example, whilst data emerging from a range of 11C-PIB studies demonstrates quantitative determination of brain Abeta non-invasively, therefore allowing monitoring of potential anti-amyloid therapeutic agents, the very short half-life of 11C, precludes widespread application of 11C-PIB in a relevant fashion in clinical settings. 11C-PIB requires not only a very expensive PET scanner (cost ˜$2M) but also an in situ cyclotron (cost ˜$2M) for the production of the radio-isotope 11C. The high production costs therefore preclude 11C-PIB PET scanning from having a public health impact as a widespread screening test.
Accordingly, as well as providing therapeutics for treating amyloid diseases there is also a need for new imaging agents that target the underlying pathogenic mechanisms in amyloidosis type diseases, particularly AD, for early diagnosis of such disease states.
The present inventors have developed novel metallocomplexes that act as preoccupants or blockers of metal binding sites on amyloid proteins.